PROJECT SUMMARY The objective of this research proposal is to assess changes in stress-induced dopamine function and inflammatory response with connectivity and behavioral symptoms in posttraumatic stress disorder (PTSD). Imaging studies of PTSD from our group and others have described altered activation and functional connectivity between a variety of brain regions including the medial prefrontal cortex (mPFC), amygdala, and hippocampus. Despite increasing knowledge of circuit dysfunction in PTSD, functional neuroimaging studies performed to date have not provided adequate information about neurotransmitter systems and neurobiological pathways that affect such circuits to maintain PTSD symptoms. PTSD is an important public health problem that affects 7 to 8 % of the general population with higher rates of occurrence in victims of sexual abuse (10%). Psychosocial stress and trauma activate neuroendocrine and immune systems and elevate circulating concentrations of inflammatory markers. Activation of the immune system and release of inflammatory cytokines disrupts the mesocortical/limbic dopamine system and are associated with symptoms of anxiety, re-experiencing, arousal and avoidance that are prominent in PTSD. Findings from our group demonstrate blunted release of dopamine, as measured by microdialysis, in a cytokine-induced inflammatory animal models. Elevated inflammatory markers (e.g. plasma CRP and cytokines) were also associated with disrupted mesolimbic and mesocortical circuits, including decreased ventral striatum and amygdala to mPFC functional connectivity, in association with symptoms of anxiety in major depressive disorder, and particularly in patients with comorbid PTSD. Functional brain imaging studies to date have outlined a neural circuitry of PTSD but these imaging measures provide only general measures of brain function (e.g. blood flow) and do not address specific neurochemical pathways. The proposed research will address this knowledge gap by examining the following questions 1) Is stress-induced prefrontal and limbic DA neurotransmission reduced in patients with PTSD?, 2) Are stress-induced inflammatory biomarkers higher in PTSD and associated with symptom severity? and 3) Are disruptions in resting measures of functional behavior and connectivity associated with PTSD and symptom severity? Our proposed work builds on our laboratory?s experience in imaging PTSD including demonstration of blood flow and blood oxygen level-dependent reductions in mPFC function. Our long-term goal is to improve our mechanistic framework of stress-induced dopaminergic function and the inflammatory response in PTSD, and to identify mechanisms that can predict PTSD symptoms and their severity that may improve future treatment approaches.